The present invention is directed to enhanced stability concentrate esmolol formulations. More specifically, the invention is directed to a concentrate esmolol formulation stabilized with benzyl alcohol. The compositions of the present invention are also suitable as multiple-dose compositions. Additionally, the present invention is directed to ready-to-use, diluted compositions made by dilution of the concentrate esmolol compositions of the present invention.
Esmolol (and its pharmaceutically acceptable salts, e.g., hydrochloride salt) and related compounds have β-adrenergic blocking activity. β-blockers are therapeutically effective agents for the treatment and prophylaxis of cardiac disorders when administered in the appropriate dosage. Esmolol, which is a short-acting β-blocker, is often times used in acute care settings to control the heart rate of a patient. The short acting property of esmolol is due to its rapid hydrolysis of the labile aliphatic methyl ester group in the blood.
Ready-to-use isotonic, and concentrate formulations, of esmolol are disclosed in U.S. Pat. Nos. 5,017,609, 6,310,094, and 6,528,540, incorporated herein by reference. Methods for making esmolol and methods for treatment or prophylaxis of cardiac disorders using such compounds are disclosed in U.S. Pat. Nos. 4,387,103, and 4,593,119, incorporated herein by reference. A current commercial esmolol concentrate formulation, covered under U.S. Pat. No. 5,017,609, comprises about 250 mg/ml of esmolol hydrochloride, 25% by volume ethanol, 25% by volume propylene glycol, 17 mg/ml sodium acetate trihydrate, and 0.715% by volume of glacial acetic acid. This composition is not intended for direct injection but for subsequent dilution with a suitable diluent.
The stability of esmolol hydrochloride {methyl3-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionate hydrochloride} in water is mediated by the rate of acid/base catalyzed hydrolysis of the labile aliphatic methyl ester group and it degrades into ASL-8123 {methyl3-[4-[2-hydroxy-3-(isopropylamino) propoxy]phenyl]propionic acid}. Ready-to-use isotonic formulations address some of the stability issues in a truly aqueous formulation and has only one degradant, ASL-8123. The current commercial concentrate formulation employs excipients (ethanol and propylene glycol) to stabilize the hydrolytic reaction, but those excipients leads to the formation of other related ester degradants. Therefore, the current commercial esmolol concentrate formulation under long term storage conditions results in the formation of ethyl and propoyl esters of esmolol in addition to ASL-8123. Furthermore the excipients (ethanol and propylene glycol) used to stabilize the current commercial esmolol concentrate formulation have been associated with potential injection site pain or irritation.
Therefore, it would be desirable to provide a stabilized concentrate esmolol composition that eliminates the formation of related ester degradants, does not include potentially irritating propylene glycol and ethanol excipients, is simpler to make than the prior art concentrate composition and, optionally, can be preserved rendering it applicable for multiple-dose use.